PROJECT SUMMARY/ABSTRACT: The societal burden of Alzheimer's disease (AD) is expected to rise, and in the absence of effective preventive measures, more than 13 million Americans are projected to have AD by 2050. The prevailing understanding of AD is that amyloid beta (A?) deposition in the brain leads to AD and that modifying A? deposition may prevent, slow, or arrest AD. In addition to A? deposition, individuals with AD often suffer from vascular disease. Although the majority of brain large artery studies have focused on intracranial large artery atherosclerosis (ILAA), ILAA is not the only brain large artery phenotype that relates to AD. Dolichoectasia, on the other hand, is a form of non-atherosclerotic brain arterial aging (BAA) phenotype that consists of dilatation and/or tortuosity. Brain arterial dilatation, dolichoectasia being its most pathological form, is associated with hypertension in the general population, connective tissue disorders, HIV, and aging. We thus propose a change in the paradigm of brain large artery disease that goes beyond atherosclerosis and/or stenosis, and incorporates non-atherosclerotic BAA as a distinct pathological phenotype. We have demonstrated that non- atherosclerotic BAA relates to Alzheimer pathology independent of atherosclerosis and brain infarcts. We have gathered preliminary data showing that brain arterial diameters are associated non-linearly with cognition, so that individuals with narrowed or dilated brain arteries have poorer cognitive performance compared with those with average arterial diameters. This proposal aims to elucidate whether BAA modifies the susceptibility to dementia via arteriolar/capillary dysfunction, neuronal/white matter damage, and/or directly via A?/tau metabolism. Aim 1 leverages an existing population-based cohort to obtain an MRI measure of non- atherosclerotic BAA and relate to ipsilateral marker of neurodegeneration. Aim 2 focuses on identifying specific cellular and structural changes that relate to non-atherosclerotic BAA with a precision so far not available in living individuals using the gold standard. In Aim 3, using transgenic AD mice, we will model BAA to validate the biological principle that non-atherosclerotic BAA can cause aging of distal arterioles and promote parenchymal degeneration, exploring potential therapeutic targets. The paradigm presented here has no precedent in the field of brain arterial remodeling. We propose not only to study BAA with unprecedented depth and resources but also to contextualize it with translatable imaging traits that may further evolve this field.